Background: Acne vulgaris (AV) is a highly prevalent skin inflammatory disorder. Histone modifications are common epigenetic processes, which happen secondary to environmental conditions. One of the many biological pathways' epigenetic regulation mechanisms is histone acetylation and deacetylation. Objective: To evaluate the serum levels of histone deacetylase 1 (HDAC1) enzyme in AV cases and to examine their correlation with AV severity. Patients and Methods: A case-control study was conducted on 90 participants: 45 patients with acne vulgaris and 45 healthy controls (HC). Global acne grading system (GAGS) was calculated. Then, serum HDAC1 level was measured by using ELISA. Results: Cases showed significantly higher HDAC1 level when compared to control group. HDAC1 among case group showed a significant gradual increase in mild, moderate, severe, and very severe grades. Moreover, positive significant correlation with the score of acne vulgaris was demonstrated (p < 0.001). Conclusion: Human histone deacetylases1 (HDAC1) appears to be dysregulated in cases with AV. This could suggest a possible therapeutic opportunity for HDAC inhibitors for AV management.